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1.  An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease 
Background: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.
Purpose: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.
Methods: An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards.
Results: We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality.
Conclusions: Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.
PMCID: PMC4098112  PMID: 24787074
2.  Alternatives to the Six-Minute Walk Test in Pulmonary Arterial Hypertension 
PLoS ONE  2014;9(8):e103626.
The physiological response during the endurance shuttle walk test (ESWT), the cycle endurance test (CET) and the incremental shuttle walk test (ISWT) remains unknown in PAH. We tested the hypothesis that endurance tests induce a near-maximal physiological demand comparable to incremental tests. We also hypothesized that differences in respiratory response during exercise would be related to the characteristics of the exercise tests.
Within two weeks, twenty-one PAH patients (mean age: 54(15) years; mean pulmonary arterial pressure: 42(12) mmHg) completed two cycling exercise tests (incremental cardiopulmonary cycling exercise test (CPET) and CET) and three field tests (ISWT, ESWT and six-minute walk test (6MWT)). Physiological parameters were continuously monitored using the same portable telemetric device.
Peak oxygen consumption (VO2peak) was similar amongst the five exercise tests (p = 0.90 by ANOVA). Walking distance correlated markedly with the VO2peak reached during field tests, especially when weight was taken into account. At 100% exercise, most physiological parameters were similar between incremental and endurance tests. However, the trends overtime differed. In the incremental tests, slopes for these parameters rose steadily over the entire duration of the tests, whereas in the endurance tests, slopes rose sharply from baseline to 25% of maximum exercise at which point they appeared far less steep until test end. Moreover, cycling exercise tests induced higher respiratory exchange ratio, ventilatory demand and enhanced leg fatigue measured subjectively and objectively.
Endurance tests induce a maximal physiological demand in PAH. Differences in peak respiratory response during exercise are related to the modality (cycling vs. walking) rather than the progression (endurance vs. incremental) of the exercise tests.
PMCID: PMC4128819  PMID: 25111294
4.  Tolerance and Physiological Correlates of Neuromuscular Electrical Stimulation in COPD: A Pilot Study 
PLoS ONE  2014;9(5):e94850.
Neuromuscular electrical stimulation (NMES) of the lower limbs is an emerging training strategy in patients with COPD. The efficacy of this technique is related to the intensity of the stimulation that is applied during the training sessions. However, little is known about tolerance to stimulation current intensity and physiological factors that could determine it. Our goal was to find potential physiological predictors of the tolerance to increasing NMES stimulation intensity in patients with mild to severe COPD.
20 patients with COPD (FEV1 = 54±14% pred.) completed 2 supervised NMES sessions followed by 5 self-directed sessions at home and one final supervised session. NMES was applied simultaneously to both quadriceps for 45 minutes, at a stimulation frequency of 50 Hz. Spirometry, body composition, muscle function and aerobic capacity were assessed at baseline. Cardiorespiratory responses, leg discomfort, muscle fatigue and markers of systemic inflammation were assessed during or after the last NMES session. Tolerance to NMES was quantified as the increase in current intensity from the initial to the final NMES session (ΔInt).
Mean ΔInt was 12±10 mA. FEV1, fat-free-mass, quadriceps strength, aerobic capacity and leg discomfort during the last NMES session positively correlated with ΔInt (r = 0.42 to 0.64, all p≤0.06) while post/pre NMES IL-6 ratio negatively correlated with ΔInt (r = −0.57, p = 0.001). FEV1, leg discomfort during last NMES session and post/pre IL-6 ratio to NMES were independent factors of variance in ΔInt (r2 = 0.72, p = 0.001).
Lower tolerance to NMES was associated with increasing airflow obstruction, low tolerance to leg discomfort during NMES and the magnitude of the IL-6 response after NMES.
Trial Registration NCT00809120
PMCID: PMC4015894  PMID: 24817528
5.  The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: Patient Characterization Phase of a Randomized Clinical Trial 
PLoS ONE  2014;9(5):e96574.
To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls.
Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests.
Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001).
Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls.
Trial Registration NCT01072396
PMCID: PMC4006871  PMID: 24788342
6.  Regenerative defect in vastus lateralis muscle of patients with chronic obstructive pulmonary disease 
Respiratory Research  2014;15(1):35.
Impaired skeletal muscle regeneration could contribute to the progression of muscle atrophy in patients with chronic obstructive pulmonary disease (COPD).
Satellite cells and myogenesis-related proteins were compared between healthy subjects and patients with COPD, with or without muscle atrophy. Satellite cells were isolated and cultured to assess their proliferative and differentiation aptitudes.
Although satellite cell numbers in muscle samples were similar between groups, the proportion of muscle fibers with central nuclei was increased in COPD. In muscle homogenates, increased expression of MyoD and decreased expression of myogenin and MRF4 were observed in COPD. In cultured satellite cells of patients with COPD, increased protein content was observed for Pax7, Myf5 (proliferation phase) and myogenin (differentiation phase) while myosin heavy chain protein content was significantly lower during differentiation.
In COPD, the number of central nuclei was increased in muscle fibers suggesting a greater number of attempts to regenerate muscle tissue than in healthy subjects. Myogenesis signaling was also altered in muscle homogenates in patients with COPD and there was a profound reduction in the differentiation potential in this population as indicated by a reduced ability to incorporate myosin heavy chain into newly formed myotubes. Collectively, these results indicate that skeletal muscle regenerative capacity termination is impaired in COPD and could contribute to the progression of muscle atrophy progression in this population.
PMCID: PMC3987676  PMID: 24666540
Satellite cells; COPD; Muscle; Regeneration; Atrophy
7.  Feasibility and effectiveness of a home-based exercise training program before lung resection surgery 
Patients with lung cancer often experience a reduction in exercise tolerance, muscle weakness and decreased quality of life. Although the effectiveness of pulmonary rehabilitation programs is well recognized in other forms of cancers and in many pulmonary diseases, few researchers have studied its impact in patients with lung cancer, particularly in those awaiting lung resection surgery (LRS).
To investigate the feasibility of a short, home-based exercise training program (HBETP) with patients under investigation for non-small cell lung cancer and potential candidates for LRS, and to determine the effectiveness of this program on exercise tolerance, skeletal muscle strength and quality of life.
Sixteen patients with lung cancer awaiting LRS participated in a four-week HBETP including moderate aerobic activities (walking and cycling) and muscle training performed three times weekly. Before and after the intervention, a cardiopulmonary exercise test, a 6 min walk test and the assessment of muscle strength and quality of life were performed.
Thirteen patients completed the four-week HBETP and all the patients completed >75% of the prescribed exercise sessions. The duration of the cycle endurance test (264±79 s versus 421±241 s; P<0.05) and the 6 min walk test distance (540±98 m versus 568±101 m; P<0.05) were significantly improved. Moreover, the strength of the deltoid, triceps and hamstrings were significantly improved (Δ post-pre training 1.82±2.83 kg, 1.32±1.75 kg and 3.41±3.7 kg; P<0.05, respectively).
In patients with lung cancer awaiting LRS, HBETP was feasible and improved exercise tolerance and muscle strength. This may be clinically relevant because poor exercise capacity and muscle weakness are predictors of postoperative complications.
PMCID: PMC3630051  PMID: 23616972
Exercise; Exercise tolerance; Home-based pulmonary rehabilitation; Lung cancer; Muscle strength; Quality of life; Training
8.  Pathogenesis of hyperinflation in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable lung disease characterized by airflow limitation that is not fully reversible. In a significant proportion of patients with COPD, reduced lung elastic recoil combined with expiratory flow limitation leads to lung hyperinflation during the course of the disease. Development of hyperinflation during the course of COPD is insidious. Dynamic hyperinflation is highly prevalent in the advanced stages of COPD, and new evidence suggests that it also occurs in many patients with mild disease, independently of the presence of resting hyperinflation. Hyperinflation is clinically relevant for patients with COPD mainly because it contributes to dyspnea, exercise intolerance, skeletal muscle limitations, morbidity, and reduced physical activity levels associated with the disease. Various pharmacological and nonpharmacological interventions have been shown to reduce hyperinflation and delay the onset of ventilatory limitation in patients with COPD. The aim of this review is to address the more recent literature regarding the pathogenesis, assessment, and management of both static and dynamic lung hyperinflation in patients with COPD. We also address the influence of biological sex and obesity and new developments in our understanding of hyperinflation in patients with mild COPD and its evolution during progression of the disease.
PMCID: PMC3933347  PMID: 24600216
chronic obstructive pulmonary disease; hyperinflation; expiratory flow limitation; operational lung volumes
9.  Preserved function and reduced angiogenesis potential of the quadriceps in patients with mild COPD 
Respiratory Research  2014;15(1):4.
Little is known about limb muscle abnormalities in mild COPD. Inactivity and systemic inflammation could play a role in the development of limb muscle dysfunction in COPD. The objective of the present study was to characterize quadriceps function, enzymatic activities and morphometry, levels of plasma inflammatory markers and physical activity levels in daily life (PAdl) in patients with mild COPD (GOLD 1).
Mid-thigh muscle cross-sectional area (MTCSA), quadriceps strength, endurance, fiber-type distribution, capillarity, pro-angiogenesis factors (VEGF-A, angiopoietin I and II) and muscle oxidative capacity were assessed in 37 patients with mild COPD and 19 controls. Systemic inflammatory markers (CRP, IL-6, TNF-α, Fibrinogen, SP-D) and PAdl were assessed.
MTCSA, quadriceps strength and endurance were not different between COPD and controls. Capillarity and muscle oxidative capacity were all preserved in mild COPD. Reduced pro-angiogenesis factor mRNA expression was seen in COPD. The level of moderately active intensity (>3 METs) was significantly lower in mild COPD and, in multiple regression analyses, the level of physical activity was a determinant of muscle oxidative capacity and capillarization. No between-group differences were found regarding muscle oxidative stress while circulating IL-6 levels were elevated in mild COPD.
The quadriceps muscle function was preserved in mild COPD although a reduced potential for angiogenesis was found. The reduced level of daily activities and evidence of systemic inflammation in these individuals suggest that these factors precede the development of overt limb muscle dysfunction in COPD.
PMCID: PMC3898018  PMID: 24438094
Chronic obstructive pulmonary disease; Muscle; Muscle biopsy; Capillarization
10.  Validation of a new questionnaire with generic and disease-specific qualities: The McGill COPD Quality of Life Questionnaire 
A validated health-related quality of life questionnaire in chronic obstructive pulmonary disease (COPD) with advantages of both generic- and disease-specific questionnaires is needed to capture patients’ perspectives of severity and impact of the disease. The McGill COPD questionnaire was created to include these advantages in English and French. It assesses three domains: symptoms, physical function and feelings with 29 items (12 from the 36-item Short-Form Health Survey with 17 from the previously developed COPD-specific module).
To evaluate the psychometric properties of this newly developed hybrid questionnaire in subjects with COPD.
Data from a multicentre, prospective cohort study involving four hospitals with COPD subjects undergoing pulmonary rehabilitation were used. Patient evaluations included health-related quality of life (the new McGill COPD questionnaire, the St Georges Respiratory Questionnaire and the 36-item Short-Form Health Survey) and pulmonary function tests pre-and postrehabilitation. Reliability, validity and responsiveness were tested.
The study included 246 COPD subjects (111 females) with a mean age of 66 years, 87% ex- and 8% current smokers (mean 61 pack-years) and mean forced expiratory volume in 1 s of 1.12 L (Global initiative for chronic Obstructive Lung Disease stages: 2, 27%; 3, 33%; and 4, 37%). Missing data were <2% and floor and ceiling effects were <5%. Internal consistency (Cronbach’s alpha) was 0.68 to 0.82. Test-retest reliability (intracorrelation coefficients) ranged from 0.74 to 0.96 for the sub-scales, and 0.95 for the total score. Correlation with the St George’s Respiratory Questionnaire was moderately high (r=− 0.88 [95% CI −0.91 to −0.84]), consistent with the a priori hypothesis for convergent validity. The effect size was 0.33 (pre-postrehabilitation mean score difference = 6), suggesting a small to moderate change.
The new McGill COPD questionnaire showed high internal consistency, test-retest reliability, validity and moderate responsiveness in COPD subjects.
PMCID: PMC3603761  PMID: 23248800
COPD; Disease-specific; Generic; Health-related quality of life; Hybrid; Psychometric property; Quality of life
11.  Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized, double-blind study 
Respiratory Research  2013;14(1):64.
We investigated the efficacy and safety of AZD3199, a novel inhaled ultra-LABA, with the main aim of establishing a dose that would maintain 24-hour bronchodilation in patients with COPD.
Patients (n = 329) were randomized to AZD3199 (200, 400 or 800 μg o.d.), formoterol (9 μg b.i.d.) or placebo via Turbuhaler® in a parallel group study. The primary objective of the study was to compare the clinical efficacy of three doses of AZD3199 inhaled once daily with 9 μg formoterol twice daily and placebo, over a 4-week treatment period in adults with moderate-to-severe COPD. After 4 weeks, peak (0–4 h) and trough (24–26 h) forced expiratory volume in 1 second (FEV1) were assessed as the primary efficacy outcome variables.
All AZD3199 doses significantly increased mean peak and trough FEV1 versus placebo (106–171 ml and 97–110 ml increases, respectively), but with no clear dose–response; the level of bronchodilation was comparable to or greater than that achieved with formoterol. Forced vital capacity (FVC) at peak bronchodilation also significantly increased with AZD3199 versus placebo (153–204 ml). COPD symptom scores and reliever use were reduced with AZD3199, while FEV1 reversibility was unaltered. Adverse events were mild-to-moderate, with no safety concerns identified. Drug exposure was dose-proportional, but lower than predicted from healthy volunteers.
All three doses of AZD3199 produced 24-hour bronchodilation, but with no clear dose–response, suggesting that doses of 200 μg or less may be sufficient to maintain bronchodilation over 24 hours in patients with COPD. No safety concerns were identified. Further studies are required to determine the once-daily AZD3199 dose for COPD.
Trial registration, NCT00929708
PMCID: PMC3691744  PMID: 23731768
Bronchodilation; β2-agonist; COPD; Once-daily; Ultra long-acting
12.  Validity of chronic obstructive pulmonary disease diagnoses in a large administrative database 
Administrative databases are often used for research purposes, with minimal attention devoted to the validity of the included diagnoses.
To determine whether the principal diagnoses of chronic obstructive pulmonary disease (COPD) made in hospitalized patients and recorded in a large administrative database are valid.
The medical charts of 1221 patients hospitalized in 40 acute care centres in Quebec and discharged between April 1, 2003 and March 31, 2004, with a principal discharge diagnosis of COPD (International Classification of Diseases, Ninth Revision codes 491, 492 or 496) were reviewed. The diagnosis of COPD was independently adjudicated by two pulmonologists using clinical history (including smoking status) and spirometry. The primary outcome measure was the positive predictive value (PPV) of the database for the diagnosis of COPD (ie, the proportion of patients with an accurate diagnosis of COPD corroborated by clinical history and spirometry).
The diagnosis of COPD was validated in 616 patients (PPV 50.4% [95% CI 47.7% to 53.3%]), with 372 patients (30.5%) classified as ‘indeterminate’. Older age and female sex were associated with a lower probability of an accurate diagnosis of COPD. Hospitalization in a teaching institution was associated with a twofold increase in the probability of a correct diagnosis.
The results support the routine ascertainment of the validity of diagnoses before using administrative databases in clinical and health services research.
PMCID: PMC3373291  PMID: 22536584
Chronic obstructive lung disease; Database; Epidemiology; Validity
13.  Responsiveness of Various Exercise-Testing Protocols to Therapeutic Interventions in COPD 
Pulmonary Medicine  2013;2013:410748.
Exercise intolerance is a key element in the pathophysiology and course of Chronic Obstructive Pulmonary Disease (COPD). As such, evaluating exercise tolerance has become an important part of the management of COPD. A wide variety of exercise-testing protocols is currently available, each protocol having its own strengths and weaknesses relative to their discriminative, methodological, and evaluative characteristics. This paper aims to review the responsiveness of several exercise-testing protocols used to evaluate the efficacy of pharmacological and nonpharmacological interventions to improve exercise tolerance in COPD. This will be done taking into account the minimally important difference, an important concept in the interpretation of the findings about responsiveness of exercise testing protocols. Among the currently available exercise-testing protocols (incremental, constant work rate, or self-paced), constant work rate exercise tests (cycle endurance test and endurance shuttle walking test) emerge as the most responsive ones for detecting and quantifying changes in exercise capacity after an intervention in COPD.
PMCID: PMC3569936  PMID: 23431439
14.  Unusual respiratory manifestations in two young adults with Duchenne muscular dystrophy 
Adult respirologists are often involved in the evaluation and treatment of young adult patients with Duchenne muscular dystrophy. In this context, the most frequent respiratory complication is nocturnal and daytime hypoventilation related to respiratory muscle weakness. The present article describes cases of Duchenne muscular dystrophy involving two brothers, 17 and 19 years of age, respectively, who presented with less frequently reported respiratory complications of their disease: obstructive sleep apnea and Cheyne-Stokes respiration with central apnea, which were believed to be partially or completely related to congestive cardiomyopathy.
PMCID: PMC3299052  PMID: 22332132
Cheynes-Stokes respiration; Duchenne muscular dystrophy; Sleep apnea
15.  Home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline 
Preventive airway management and home mechanical ventilation (HMV) is a complex, interdisciplinary component of respiratory care and clinical practice. However, the rising costs of hospital care and the advent of commercially available equipment, coupled with the desire of individuals to maintain an in-home quality of life has fuelled the demand for HMV. The Canadian Thoracic Society HMV Guidelines Committee developed this up-to-date, evidence-based, clinical practice guideline as a resource for physicians, health care providers, policy makers and patients at risk for or currently using ventilatory support in the home.
Increasing numbers of patients are surviving episodes of prolonged mechanical ventilation or benefitting from the recent availability of user-friendly noninvasive ventilators. Although many publications pertaining to specific aspects of home mechanical ventilation (HMV) exist, very few comprehensive guidelines that bring together all of the current literature on patients at risk for or using mechanical ventilatory support are available. The Canadian Thoracic Society HMV Guideline Committee has reviewed the available English literature on topics related to HMV in adults, and completed a detailed guideline that will help standardize and improve the assessment and management of individuals requiring noninvasive or invasive HMV. The guideline provides a disease-specific review of illnesses including amyotrophic lateral sclerosis, spinal cord injury, muscular dystrophies, myotonic dystrophy, kyphoscoliosis, post-polio syndrome, central hypoventilation syndrome, obesity hypoventilation syndrome, and chronic obstructive pulmonary disease as well as important common themes such as airway clearance and the process of transition to home. The guidelines have been extensively reviewed by international experts, allied health professionals and target audiences. They will be updated on a regular basis to incorporate any new information.
PMCID: PMC3205101  PMID: 22059178
Airway clearance strategies; Amyotrophic lateral sclerosis; Central hypoventilation syndrome; Chronic obstructive pulmonary diseases; Duchenne muscular dystrophy; Ethics; Home mechanical ventilation; Kyphoscoliosis; Muscular dystrophies; Myopathies; Myotonic dystrophy; Obesity hypoventilation syndrome; Post-polio syndrome; Prolonged mechanical ventilation; Spinal cord injury; Steinert’s muscular dystrophy; Transition to home
16.  Satellite Cells Senescence in Limb Muscle of Severe Patients with COPD 
PLoS ONE  2012;7(6):e39124.
The maintenance of peripheral muscle mass may be compromised in chronic obstructive pulmonary disease (COPD) due to premature cellular senescence and exhaustion of the regenerative potential of the muscles.
Vastus lateralis biopsies were obtained from patients with COPD (n = 16) and healthy subjects (n = 7). Satellite cell number and the proportion of central nuclei, as a marker of muscle regenerative events, were assessed on cryosections. Telomere lengths, used as a marker of cellular senescence, were determined using Southern blot analyses.
Central nuclei proportion was significantly higher in patients with COPD with a preserved muscle mass compared to controls and patients with COPD with muscle atrophy (p<0.001). In COPD, maximal telomere length was significantly decreased compared to controls (p<0.05). Similarly, minimal telomere length was significantly reduced in GOLD III–IV patients with muscle atrophy compared to controls (p<0.005). Minimal, mean and maximum telomere lengths correlated with mid-thigh muscle cross-sectional area (MTCSA) (R = 0.523, p = 0.005; R = 0.435, p = 0.019 and R = 0.491, p = 0.009, respectively).
Evidence of increased regenerative events was seen in GOLD III–IV patients with preserved muscle mass. Shortening of telomeres in GOLD III–IV patients with muscle atrophy is consistent with an increased number of senescent satellite cells and an exhausted muscle regenerative capacity, compromising the maintenance of muscle mass in these individuals.
PMCID: PMC3374758  PMID: 22720047
17.  Assessment of Daily Life Physical Activities in Pulmonary Arterial Hypertension 
PLoS ONE  2011;6(11):e27993.
In pulmonary arterial hypertension (PAH), the six-minute walk test (6MWT) is believed to be representative of patient's daily life physical activities (DLPA). Whether DLPA are decreased in PAH and whether the 6MWT is representative of patient's DLPA remain unknown.
15 patients with idiopathic PAH (IPAH) and 10 patients with PAH associated with limited systemic sclerosis (PAH-SSc) were matched with 15 healthy control subjects and 10 patients with limited systemic sclerosis without PAH. Each subject completed a 6MWT. The mean number of daily steps and the mean energy expenditure and duration of physical activities >3 METs were assessed with a physical activity monitor for seven consecutive days and used as markers of DLPA.
The mean number of daily steps and the mean daily energy expenditure and duration of physical activities >3 METs were all reduced in PAH patients compared to their controls (all p<0.05). The mean number of daily steps correlated with the 6MWT distance for both IPAH and PAH-SSc patients (r = 0.76, p<0.01 and r = 0.85, p<0.01), respectively.
DLPA are decreased in PAH and correlate with the 6MWT distance. Functional exercise capacity may thus be a useful surrogate of DLPA in PAH.
PMCID: PMC3218075  PMID: 22110770
18.  Variability of protein level and phosphorylation status caused by biopsy protocol design in human skeletal muscle analyses 
BMC Research Notes  2011;4:488.
Bergström needle biopsy is widely used to sample skeletal muscle in order to study cell signaling directly in human tissue. Consequences of the biopsy protocol design on muscle protein quantity and quality remain unclear. The aim of the present study was to assess the impact of different events surrounding biopsy protocol on the stability of the Western blot signal of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, glycogen synthase kinase-3β (GSK-3β), muscle RING finger protein 1 (MuRF1) and p70 S6 kinase (p70 S6K). Six healthy subjects underwent four biopsies of the vastus lateralis, distributed into two distinct visits spaced by 48 hrs. At visit 1, a basal biopsy in the right leg was performed in the morning (R1) followed by a second in the left leg in the afternoon (AF). At visit 2, a second basal biopsy (R2) was collected from the right leg. Low intensity mobilization (3 × 20 right leg extensions) was performed and a final biopsy (Mob) was collected using the same incision site as R2.
Akt and p70 S6K phosphorylation levels were increased by 83% when AF biopsy was compared to R1. Mob condition induced important phosphorylation of p70 S6K when compared to R2. Comparison of R1 and R2 biopsies revealed a relative stability of the signal for both total and phosphorylated proteins.
This study highlights the importance to standardize muscle biopsy protocols in order to minimize the method-induced variation when analyzing Western blot signals.
PMCID: PMC3225408  PMID: 22075211
19.  Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8+ T cells in chronic obstructive pulmonary disease 
Respiratory Research  2011;12(1):149.
Cigarette smoke is a major risk factor for chronic obstructive pulmonary disease (COPD), an inflammatory lung disorder. COPD is characterized by an increase in CD8+ T cells within the central and peripheral airways. We hypothesized that the CD8+ T cells in COPD patients have increased Toll-like receptor (TLR) expression compared to control subjects due to the exposure of cigarette smoke in the airways.
Endobronchial biopsies and peripheral blood were obtained from COPD patients and control subjects. TLR4 and TLR9 expression was assessed by immunostaining of lung tissue and flow cytometry of the peripheral blood. CD8+ T cells isolated from peripheral blood were treated with or without cigarette smoke condensate (CSC) as well as TLR4 and TLR9 inhibitors. PCR and western blotting were used to determine TLR4 and TLR9 expression, while cytokine secretion from these cells was detected using electrochemiluminescence technology.
No difference was observed in the overall expression of TLR4 and TLR9 in the lung tissue and peripheral blood of COPD patients compared to control subjects. However, COPD patients had increased TLR4 and TLR9 expression on lung CD8+ T cells. Exposure of CD8+ T cells to CSC resulted in an increase of TLR4 and TLR9 protein expression. CSC exposure also caused the activation of CD8+ T cells, resulting in the production of IL-1β, IL-6, IL-10, IL-12p70, TNFα and IFNγ. Furthermore, inhibition of TLR4 or TLR9 significantly attenuated the production of TNFα and IL-10.
Our results demonstrate increased expression of TLR4 and TLR9 on lung CD8+ T cells in COPD. CD8+ T cells exposed to CSC increased TLR4 and TLR9 levels and increased cytokine production. These results provide a new perspective on the role of CD8+ T cells in COPD.
PMCID: PMC3260101  PMID: 22070100
COPD; Toll-like receptors; CD8+ T cell; cigarette smoke; cytokine
20.  CD8 positive T cells express IL-17 in patients with chronic obstructive pulmonary disease 
Respiratory Research  2011;12(1):43.
Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease of the lung. The nature of the immune reaction in COPD raises the possibility that IL-17 and related cytokines may contribute to this disorder. This study analyzed the expression of IL-17A and IL-17F as well as the phenotype of cells producing them in bronchial biopsies from COPD patients.
Bronchoscopic biopsies of the airway were obtained from 16 COPD subjects (GOLD stage 1-4) and 15 control subjects. Paraffin sections were used for the investigation of IL-17A and IL-17F expression in the airways by immunohistochemistry, and frozen sections were used for the immunofluorescence double staining of IL-17A or IL-17F paired with CD4 or CD8. In order to confirm the expression of IL-17A and IL-17F at the mRNA level, a quantitative RT-PCR was performed on the total mRNA extracted from entire section or CD8 positive cells selected by laser capture microdissection.
IL-17F immunoreactivity was significantly higher in the bronchial biopsies of COPD patients compared to control subjects (P < 0.0001). In the submucosa, the absolute number of both IL-17A and IL-17F positive cells was higher in COPD patients (P < 0.0001). After adjusting for the total number of cells in the submucosa, we still found that more cells were positive for both IL-17A (P < 0.0001) and IL-17F (P < 0.0001) in COPD patients compared to controls. The mRNA expression of IL-17A and IL-17F in airways of COPD patients was confirmed by RT-PCR. The expression of IL-17A and IL-17F was co-localized with not only CD4 but also CD8, which was further confirmed by RT-PCR on laser capture microdissection selected CD8 positive cells.
These findings support the notion that Th17 cytokines could play important roles in the pathogenesis of COPD, raising the possibility of using this mechanism as the basis for novel therapeutic approaches.
PMCID: PMC3082241  PMID: 21477350
Chronic Obstructive Pulmonary Disease; IL-17; Tc17 cells
21.  Physiological Correlates of Endurance Time Variability during Constant-Workrate Cycling Exercise in Patients with COPD 
PLoS ONE  2011;6(2):e17007.
The endurance time (Tend) during constant-workrate cycling exercise (CET) is highly variable in COPD. We investigated pulmonary and physiological variables that may contribute to these variations in Tend.
Ninety-two patients with COPD completed a CET performed at 80% of peak workrate capacity (Wpeak). Patients were divided into tertiles of Tend [Group 1: <4 min; Group 2: 4–6 min; Group 3: >6 min]. Disease severity (FEV1), aerobic fitness (Wpeak, peak oxygen consumption [peak], ventilatory threshold [VT]), quadriceps strength (MVC), symptom scores at the end of CET and exercise intensity during CET (heart rate at the end of CET to heart rate at peak incremental exercise ratio [HRCET/HRpeak]) were analyzed as potential variables influencing Tend.
Wpeak, peak, VT, MVC, leg fatigue at end of CET, and HRCET/HRpeak were lower in group 1 than in group 2 or 3 (p≤0.05). VT and leg fatigue at end of CET independently predicted Tend in multiple regression analysis (r = 0.50, p = 0.001).
Tend was independently related to the aerobic fitness and to tolerance to leg fatigue at the end of exercise. A large fraction of the variability in Tend was not explained by the physiological parameters assessed in the present study. Individualization of exercise intensity during CET should help in reducing variations in Tend among patients with COPD.
PMCID: PMC3046138  PMID: 21386991
22.  The impact of obesity on walking and cycling performance and response to pulmonary rehabilitation in COPD 
We examined the influence of overweight and obesity on pulmonary function, exercise tolerance, quality of life and response to pulmonary rehabilitation in COPD.
261 patients with COPD were divided into three groups: normal body mass index (BMI), overweight and obese. Baseline and post rehabilitation pulmonary function, 6-min walking test (6MWT), endurance time during a constant workrate exercise test (CET) and St. George's Respiratory Questionnaire (SGRQ) scores were compared between all three classes of BMI.
At baseline, obese and overweight patients had less severe airflow obstruction compared to normal BMI patients. There was no baseline difference in CET performance or SGRQ scores across BMI classes and 6MWT was reduced in the presence of obesity (p < 0.01). Compared to baseline, post-rehabilitation 6MWT, CET performance and SGRQ scores improved significantly in each group (p < 0.01), but 6MWT was still significantly lower in the presence of obesity.
Walking, but not cycling performance was worse in obese patients. This difference was maintained post rehabilitation despite significant improvements. Weight excess may counterbalance the effect of a better preserved respiratory function in the performance of daily activities such as walking. However, obesity and overweight did not influence the magnitude of improvement after pulmonary rehabilitation.
PMCID: PMC2987952  PMID: 21054892
23.  Effect of obesity on constant workrate exercise in hyperinflated men with COPD 
Chronic obstructive pulmonary disease (COPD) and a high body mass index (BMI) can both affect pulmonary volumes as well as exercise tolerance, but their combined effect on these outcomes is not well known. The aim of this study was to investigate the effects of increased BMI during constant workrate cycle ergometry in patients with COPD.
Men with COPD and hyperinflation were divided according to World Health Organization BMI classification: 84 normal BMI (NBMI), 130 overweight (OW) and 64 obese (OB). Patients underwent spirometric and lung volumes assessment and an incremental cycling exercise test. This was followed by a constant workrate exercise test (CET) at 75% of peak capacity. Inspiratory capacity and Borg dyspnea scores were measured at baseline, during and at the end of CET.
Results and discussion
FEV1 % predicted was not different across BMI classes. Total lung capacity and functional residual capacity were significantly lower in OB and OW compared to NBMI patients. Peak VO2 in L·min-1 was significantly higher in OB and OW patients than in NBMI patients. CET time was not different across BMI classes (p = 0.11). Changes in lung volumes and dyspnea during CET were not different between BMI categories.
OB and OW patients with COPD had a higher peak VO2 than their lean counterparts. Endurance time, dyspnea and changes in lung volumes during CET were similar between BMI categories.
PMCID: PMC2891696  PMID: 20509967
24.  Six‐minute walking versus shuttle walking: responsiveness to bronchodilation in chronic obstructive pulmonary disease 
Thorax  2006;62(4):291-298.
The responsiveness of the endurance shuttle walk to functional changes following bronchodilation has recently been reported. The current literature suggests that the 6 min walking test (6MWT) is less responsive to bronchodilation than the endurance shuttle walk.
To compare bronchodilator‐induced changes in exercise performance with the 6MWT and the endurance shuttle walk.
In a randomised, double‐blind, placebo‐controlled, crossover trial, 14 patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 s (FEV1) 50 (8)% predicted) completed two 6MWTs and two endurance shuttle walks, each preceded by nebulised placebo or 500 μg ipratropium bromide. Cardiorespiratory parameters were monitored during each walking test with a portable telemetric gas analyser. Quadriceps twitch force was measured by magnetic stimulation of the femoral nerve before and after each walking test.
The 6 min walking distance did not change significantly after bronchodilation despite a significant increase in FEV1 of 0.18 (0.09) litres (p<0.001). A similar change in FEV1 (0.18 (0.12) litres, p<0.001) was associated with a significant improvement in the distance walked on the endurance shuttle walk (Δdistance ipratropium bromide – placebo  =  144 (219) m, p = 0.03). Quadriceps muscle fatigue was infrequent (<15% of patients) after both walking tests.
The endurance shuttle walk is more responsive than the 6MWT for detecting changes in exercise performance following bronchodilation.
PMCID: PMC2092479  PMID: 17099077
25.  Effects of aerobic exercise training and irbesartan on blood pressure and heart rate variability in patients with chronic obstructive pulmonary disease 
The present pilot study was undertaken to evaluate the efficacy of an aerobic exercise training (AET) program alone or combined with an antihypertensive agent (irbesartan) to reduce blood pressure (BP) and enhance heart rate variability (HRV) in chronic obstructive pulmonary disease patients.
Twenty-one patients were randomly assigned to a double-blind treatment with exercise and placebo (n=11) or exercise and irbesartan (n=10). Subjects underwent 24 h BP monitoring and 24 h electrocardiographic recording before and after the 12-week AET. HRV was investigated using three indexes from the power spectral analysis and three indexes calculated from the time domain. The AET program consisted of exercising on a calibrated ergocycle for 30 min three times per week. Five patients in the placebo group were excluded during follow-up because they were not compliant.
There was no change in 24 h systolic and diastolic BP before (130±14 mmHg and 70±3 mmHg, respectively) and after (128±8 mmHg and 70±8 mmHg, respectively) exercise training in the placebo group, whereas in the irbesartan group systolic and diastolic BP decreased from 135±9 mmHg and 76±9 mmHg to 126±12 mmHg and 72±8 mmHg, respectively (P<0.02). There were no changes in HRV parameters in either group.
The present study suggests that a 12-week AET program is not associated with a significant reduction in BP or enhancement in HRV, whereas an AET program combined with irbe-sartan is associated with a reduction in 24 h BP.
PMCID: PMC2679570  PMID: 18949104
Autonomic nervous system; Exercise training; Hypertension; Respiratory disease

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